Both nicotine and A9-tetrahydrocannabinol (THC) are well known to have immune suppressing properties, but no previous studies have investigated their combined effects on innate immune system function, despite the fact that most marijuana users use both drugs together. While potentially detrimental during development, the ability of both nicotine and THC to suppress immune function may be therapeutic in treating chronic pro-inflammatory diseases. For example, a growing body of evidence suggests that innate immunity is pathologically unregulated in various neurodegenerative disease states such as Alzheimer's disease (AD). Upon activation, brain immune cells, known as "microglia," release pro-inflammatory cytokines, such as TNF-a, which have been implicated in causing neuronal cell death. We recently discovered that nicotinic receptors are functionally expressed on microglia and that nicotine reduced microglial activation and enhanced microglial phagocytosis of Abeta1-42, a peptide implicated in Alzheimer's disease. In addition, we recently found that cannabinoid receptor activation similarly reduced microglial activation and enhanced microglial phagocytosis of Abeta1-42 via inhibition of the CD40 signaling pathway. Moreover, we found that the combination of nicotine and THC had dose-dependent and synergistic effects on reducing microglial activation. Therefore, we hypothesize that the combination of nicotine and THC will represent a potentially powerful therapeutic strategy against pro-inflammatory diseases like Alzheimer's disease. To test this hypothesis, we will pursue following Specific Aims to fully characterize the nicotine/THC combination in vitro and in vivo on (1) microglial activation, (2) microglial phagocytic capability, and (3) AD-like pathology and behavioral changes in Alzheimer transgenic mice. Alzheimer's disease is a devastating neurodegenerative disease that currently affects an estimated 4.5 million Americans, costing the U.S. more than $100 billion annually. Finding a treatment that could delay onset by five years could reduce the number of individuals with Alzheimer's disease by nearly 50 percent after 50 years. Our research will also lead to a better understanding of the signaling mechanisms of the innate immune system when responding to the actions of both nicotine and THC concurrently, something that is occurring already in a significant proportion of the population. [unreadable] [unreadable] [unreadable] [unreadable]